Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers

Adam Shlien (Lead / Corresponding author), Brittany B. Campbell, Richard De Borja, Ludmil B. Alexandrov, Daniele Merico, David Wedge, Peter Van Loo, Patrick S. Tarpey, Paul Coupland, Sam Behjati, Aaron Pollett, Tatiana Lipman, Abolfazl Heidari, Shriya Deshmukh, Na'ama Avitzur, Bettina Meier, Moritz Gerstung, Ye Hong, Diana M. Merino, Manasa Ramakrishna & 31 others Marc Remke, Roland Arnold, Gagan B. Panigrahi, Neha P. Thakkar, Karl P. Hodel, Erin E. Henninger, A. Yasemin Göksenin, Doua Bakry, George S. Charames, Harriet Druker, Jordan Lerner-Ellis, Matthew Mistry, Rina Dvir, Ronald Grant, Ronit Elhasid, Roula Farah, Glenn P. Taylor, Paul C. Nathan, Sarah Alexander, Shay Ben-Shachar, Simon C. Ling, Steven Gallinger, Shlomi Constantini, Peter Dirks, Annie Huang, Stephen W. Scherer, Richard G. Grundy, Carol Durno, Melyssa Aronson, Anton Gartner, for the Biallelic Mismatch Repair Deficiency Consortium

    Research output: Contribution to journalLetter

    147 Citations (Scopus)

    Abstract

    DNA replication-associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutation consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (>250/Mb), which was greater than all childhood and most cancers (>7,000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerase ε or δ. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P < 10 -13). Sequential tumor biopsy analysis revealed that bMMRD/polymerase-mutant cancers rapidly amass an excess of simultaneous mutations (∼600 mutations/cell division), reaching but not exceeding ∼20,000 exonic mutations in <6 months. This implies a threshold compatible with cancer-cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair.

    Original languageEnglish
    Pages (from-to)257-262
    Number of pages6
    JournalNature Genetics
    Volume47
    Issue number3
    DOIs
    Publication statusPublished - 2 Feb 2015

    Fingerprint

    Mutation
    Genes
    Neoplasms
    DNA Mismatch Repair
    DNA-Directed DNA Polymerase
    DNA Replication
    Germ Cells
    Brain Neoplasms
    Cell Division
    Cell Survival
    Turcot syndrome
    Genome
    Biopsy

    Cite this

    Shlien, A., Campbell, B. B., De Borja, R., Alexandrov, L. B., Merico, D., Wedge, D., ... for the Biallelic Mismatch Repair Deficiency Consortium (2015). Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. Nature Genetics, 47(3), 257-262. https://doi.org/10.1038/ng.3202
    Shlien, Adam ; Campbell, Brittany B. ; De Borja, Richard ; Alexandrov, Ludmil B. ; Merico, Daniele ; Wedge, David ; Van Loo, Peter ; Tarpey, Patrick S. ; Coupland, Paul ; Behjati, Sam ; Pollett, Aaron ; Lipman, Tatiana ; Heidari, Abolfazl ; Deshmukh, Shriya ; Avitzur, Na'ama ; Meier, Bettina ; Gerstung, Moritz ; Hong, Ye ; Merino, Diana M. ; Ramakrishna, Manasa ; Remke, Marc ; Arnold, Roland ; Panigrahi, Gagan B. ; Thakkar, Neha P. ; Hodel, Karl P. ; Henninger, Erin E. ; Göksenin, A. Yasemin ; Bakry, Doua ; Charames, George S. ; Druker, Harriet ; Lerner-Ellis, Jordan ; Mistry, Matthew ; Dvir, Rina ; Grant, Ronald ; Elhasid, Ronit ; Farah, Roula ; Taylor, Glenn P. ; Nathan, Paul C. ; Alexander, Sarah ; Ben-Shachar, Shay ; Ling, Simon C. ; Gallinger, Steven ; Constantini, Shlomi ; Dirks, Peter ; Huang, Annie ; Scherer, Stephen W. ; Grundy, Richard G. ; Durno, Carol ; Aronson, Melyssa ; Gartner, Anton ; for the Biallelic Mismatch Repair Deficiency Consortium. / Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. In: Nature Genetics. 2015 ; Vol. 47, No. 3. pp. 257-262.
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    abstract = "DNA replication-associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutation consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (>250/Mb), which was greater than all childhood and most cancers (>7,000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerase ε or δ. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P < 10 -13). Sequential tumor biopsy analysis revealed that bMMRD/polymerase-mutant cancers rapidly amass an excess of simultaneous mutations (∼600 mutations/cell division), reaching but not exceeding ∼20,000 exonic mutations in <6 months. This implies a threshold compatible with cancer-cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair.",
    author = "Adam Shlien and Campbell, {Brittany B.} and {De Borja}, Richard and Alexandrov, {Ludmil B.} and Daniele Merico and David Wedge and {Van Loo}, Peter and Tarpey, {Patrick S.} and Paul Coupland and Sam Behjati and Aaron Pollett and Tatiana Lipman and Abolfazl Heidari and Shriya Deshmukh and Na'ama Avitzur and Bettina Meier and Moritz Gerstung and Ye Hong and Merino, {Diana M.} and Manasa Ramakrishna and Marc Remke and Roland Arnold and Panigrahi, {Gagan B.} and Thakkar, {Neha P.} and Hodel, {Karl P.} and Henninger, {Erin E.} and G{\"o}ksenin, {A. Yasemin} and Doua Bakry and Charames, {George S.} and Harriet Druker and Jordan Lerner-Ellis and Matthew Mistry and Rina Dvir and Ronald Grant and Ronit Elhasid and Roula Farah and Taylor, {Glenn P.} and Nathan, {Paul C.} and Sarah Alexander and Shay Ben-Shachar and Ling, {Simon C.} and Steven Gallinger and Shlomi Constantini and Peter Dirks and Annie Huang and Scherer, {Stephen W.} and Grundy, {Richard G.} and Carol Durno and Melyssa Aronson and Anton Gartner and {for the Biallelic Mismatch Repair Deficiency Consortium}",
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    Shlien, A, Campbell, BB, De Borja, R, Alexandrov, LB, Merico, D, Wedge, D, Van Loo, P, Tarpey, PS, Coupland, P, Behjati, S, Pollett, A, Lipman, T, Heidari, A, Deshmukh, S, Avitzur, N, Meier, B, Gerstung, M, Hong, Y, Merino, DM, Ramakrishna, M, Remke, M, Arnold, R, Panigrahi, GB, Thakkar, NP, Hodel, KP, Henninger, EE, Göksenin, AY, Bakry, D, Charames, GS, Druker, H, Lerner-Ellis, J, Mistry, M, Dvir, R, Grant, R, Elhasid, R, Farah, R, Taylor, GP, Nathan, PC, Alexander, S, Ben-Shachar, S, Ling, SC, Gallinger, S, Constantini, S, Dirks, P, Huang, A, Scherer, SW, Grundy, RG, Durno, C, Aronson, M, Gartner, A & for the Biallelic Mismatch Repair Deficiency Consortium 2015, 'Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers', Nature Genetics, vol. 47, no. 3, pp. 257-262. https://doi.org/10.1038/ng.3202

    Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. / Shlien, Adam (Lead / Corresponding author); Campbell, Brittany B.; De Borja, Richard; Alexandrov, Ludmil B.; Merico, Daniele; Wedge, David; Van Loo, Peter; Tarpey, Patrick S.; Coupland, Paul; Behjati, Sam; Pollett, Aaron; Lipman, Tatiana; Heidari, Abolfazl; Deshmukh, Shriya; Avitzur, Na'ama; Meier, Bettina; Gerstung, Moritz; Hong, Ye; Merino, Diana M.; Ramakrishna, Manasa; Remke, Marc; Arnold, Roland; Panigrahi, Gagan B.; Thakkar, Neha P.; Hodel, Karl P.; Henninger, Erin E.; Göksenin, A. Yasemin; Bakry, Doua; Charames, George S.; Druker, Harriet; Lerner-Ellis, Jordan; Mistry, Matthew; Dvir, Rina; Grant, Ronald; Elhasid, Ronit; Farah, Roula; Taylor, Glenn P.; Nathan, Paul C.; Alexander, Sarah; Ben-Shachar, Shay; Ling, Simon C.; Gallinger, Steven; Constantini, Shlomi; Dirks, Peter; Huang, Annie; Scherer, Stephen W.; Grundy, Richard G.; Durno, Carol; Aronson, Melyssa; Gartner, Anton; for the Biallelic Mismatch Repair Deficiency Consortium.

    In: Nature Genetics, Vol. 47, No. 3, 02.02.2015, p. 257-262.

    Research output: Contribution to journalLetter

    TY - JOUR

    T1 - Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers

    AU - Shlien, Adam

    AU - Campbell, Brittany B.

    AU - De Borja, Richard

    AU - Alexandrov, Ludmil B.

    AU - Merico, Daniele

    AU - Wedge, David

    AU - Van Loo, Peter

    AU - Tarpey, Patrick S.

    AU - Coupland, Paul

    AU - Behjati, Sam

    AU - Pollett, Aaron

    AU - Lipman, Tatiana

    AU - Heidari, Abolfazl

    AU - Deshmukh, Shriya

    AU - Avitzur, Na'ama

    AU - Meier, Bettina

    AU - Gerstung, Moritz

    AU - Hong, Ye

    AU - Merino, Diana M.

    AU - Ramakrishna, Manasa

    AU - Remke, Marc

    AU - Arnold, Roland

    AU - Panigrahi, Gagan B.

    AU - Thakkar, Neha P.

    AU - Hodel, Karl P.

    AU - Henninger, Erin E.

    AU - Göksenin, A. Yasemin

    AU - Bakry, Doua

    AU - Charames, George S.

    AU - Druker, Harriet

    AU - Lerner-Ellis, Jordan

    AU - Mistry, Matthew

    AU - Dvir, Rina

    AU - Grant, Ronald

    AU - Elhasid, Ronit

    AU - Farah, Roula

    AU - Taylor, Glenn P.

    AU - Nathan, Paul C.

    AU - Alexander, Sarah

    AU - Ben-Shachar, Shay

    AU - Ling, Simon C.

    AU - Gallinger, Steven

    AU - Constantini, Shlomi

    AU - Dirks, Peter

    AU - Huang, Annie

    AU - Scherer, Stephen W.

    AU - Grundy, Richard G.

    AU - Durno, Carol

    AU - Aronson, Melyssa

    AU - Gartner, Anton

    AU - for the Biallelic Mismatch Repair Deficiency Consortium

    PY - 2015/2/2

    Y1 - 2015/2/2

    N2 - DNA replication-associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutation consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (>250/Mb), which was greater than all childhood and most cancers (>7,000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerase ε or δ. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P < 10 -13). Sequential tumor biopsy analysis revealed that bMMRD/polymerase-mutant cancers rapidly amass an excess of simultaneous mutations (∼600 mutations/cell division), reaching but not exceeding ∼20,000 exonic mutations in <6 months. This implies a threshold compatible with cancer-cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair.

    AB - DNA replication-associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutation consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (>250/Mb), which was greater than all childhood and most cancers (>7,000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerase ε or δ. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P < 10 -13). Sequential tumor biopsy analysis revealed that bMMRD/polymerase-mutant cancers rapidly amass an excess of simultaneous mutations (∼600 mutations/cell division), reaching but not exceeding ∼20,000 exonic mutations in <6 months. This implies a threshold compatible with cancer-cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair.

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    U2 - 10.1038/ng.3202

    DO - 10.1038/ng.3202

    M3 - Letter

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    SP - 257

    EP - 262

    JO - Nature Genetics

    JF - Nature Genetics

    SN - 1061-4036

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